Targeted radiation therapy has been a mainstay of treatment for human cancers for decades. The development of compounds that sensitize malignancies to radiation has significantly enhanced its efficacy. The ability of “radio-sensitizer” compounds to improve therapy is dependent on their entry into cancerous cells. However, the toxic effects of most radio-sensitizing compounds on the body limit their administration to patients. Therefore, there is a great need to develop novel compounds or delivery systems that boost the uptake of radio-sensitizing compounds into tumors. Improved uptake of radio-sensitizing compounds into tumors could drastically improve the response to therapy and reduce the duration of treatment.
Ephrin receptors constitute the largest family of receptor tyrosine kinases. The family consists of 16 individual receptors (14 found in mammals), which are activated by nine ephrins (8 in mammals). Eph receptors and their ephrin ligands are both anchored onto the plasma membrane and are subdivided into two subclasses, A and B. Usually, EphA receptors (EphA1-A10) interact with glycosylphosphatidylinositol (GPI)-anchored ephrin-A ligands (ephrin-A1-A6), whereas EphB receptors (EphB1-B6) interact with transmembrane ephrin-B ligands (ephrin-B1-B3) that have a short cytoplasmic portion carrying both Src homology domain 2 and PDZ domain-binding motifs. A few examples of inter-class binding have also been reported. The extensive signaling network of Ephs and their ligands plays important roles in a great variety of processes, such as regulation of cell assembly, proliferation, migration, cell attachment and shape, axon guidance and synaptic plasticity, particularly during development. Recently they were also implicated in many physiological processes, including the regulation of insulin secretion, bone homeostasis, immune function, blood clotting, etc. It is noteworthy that ephrin B2 was found to specifically bind the attachment (G) glycoproteins of Nipah virus and Hendra virus to serve as a functional receptor for the entry of both viruses in animals and humans.
It is not surprising that Ephs play important roles in tumorigenesis and metastasis. The high levels of Ephs found in cancers may generate proliferative and survival signals, and influence angiogenesis in many tumor types, including lung, breast and prostate cancers. Consequently, an ability to modulate or target this family of receptors could possess therapeutic value. Modulation can be achieved with antibodies, soluble forms of Eph receptors and ephrin extracellular domains or low molecular weight antagonists. Such modulation, largely directed at the canonical ligand-receptor signaling pathways, is complicated by bi-directional signaling that can suppress as well as stimulate cancer growth.
Fewer attempts have been made to use overexpressed Eph receptors as molecular targets for the selective delivery of anti-cancer therapeutics. Among new anticancer therapeutics, small peptides have shown considerable promise based on their potent bioactivity and superb target specificity. Although peptide-based compounds with high affinity binding to selected ephrin receptors have been reported, their anticancer potential has not been evaluated.
Azurin (Azu), a small protein produced by the bacterial pathogen Pseudomonas aeruginosa possesses significant anticancer and antiviral activity. The protein binds to selected ephrin receptors, EphB2, EphA6, and to a lesser extent to EphA4 and EphA7, primarily through a short fragment of the protein, Azu96-113. Development of therapeutic analogs of this protein are of interest.
Publications
    Castaño et al. EPH receptors in cancer, Histol. Histopathol. 2008; 23(8): 1011-23; Brannan et al. Expression of the receptor tyrosine kinase EphA2 is increased in smokers and predicts poor survival in non-small cell lung cancer, Cancer Res. 2009; 15(13):4423-30; Chaudhari et al. Cupredoxin-cancer interrelationship: azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth, Biochemistry 2007; 46(7): 1799-810.